Women who smoke face significant health disparities as they are less able to quit smoking and experience exacerbated health risk with similar levels of tobacco exposure compared to men. Contributing to these disparities, medications based on the nicotinic acetylcholine system may not be as effective for women. Negative affect and stress regulation play a key role in the maintenance of and relapse to smoking in women, whereas men are differentially sensitive to the effects of nicotine reinforcement. F^harmacotherapy development targeted toward gender-sensitive aspects of smoking is a critical, yet underdeveloped area of research. The Yale-SCOR will probe the noradrenergic system's effects on stress-reactivity and nicotine reinforcement - hypothesizing that smoking activates different brain systems modulated by noradrenergic activity in women (PFC-amygdala axis) and men (mesolimbic dopamine system), and that guanfacine (an a2a adrenergic agonist) can preferentially target these gender-sensitive systems to improve smoking cessation outcomes. Using our validated human laboratory model to examine stress-induced smoking, preliminary data indicate that guanfacine preferentially counteracted stress effects on smoking in women and attenuated nicotine reinforcement in men. During a subsequent 4-week treatment phase, guanfacine significantly reduced smoking behavior in both women and men, suggesting that guanfacine has clinical utility for both genders. With input and feedback from Projects I and II, the primary aim of Project III is to conduct a Phase II double-blind, placebo-controlled study to examine gender differences in guanfacine's effect in 1) counteracting stress-induced smoking behavior and smoking-related reinforcement in the laboratory and 2) improving clinical outcomes during a subsequent brief treatment phase. We predict that guanfacine will improve treatment outcomes in women and men by targeting gender-sensitive mechanisms - by attenuating stress reactivity in women and reducing nicotine reinforcement in men. Importantly, we will examine gender differences in mechanisms underlying stress-precipitated smoking lapse and smoking- related reinforcement (e.g., craving, mood, withdrawal, cardiovascular reactivity, hypothalamus-pituitary- adrenal (HPA) axis reactivity, catecholamines, cognitive function). The aims of Project III are highly integrated with Projects I and II, which are focused on identifying the underlying neurocircuitry and neurochemistry of guanfacine's effects on stress reactivity and nicotine reinforcement. Synthesis of findings across the three projects will identify new neurobiological targets for gender-sensitive therapeutics for smoking cessation. RELEVANCE (See instnjctions): Women have poorer rates of smoking cessation and exacerbated health risk with similar levels of tobacco exposure compared to men, yet few attempts have been made to develop gender-sensitive smoking cessation treatments. This research contributes to the public health by establishing whether guanfacine demonstrates efficacy for smoking cessation by preferentially attenuating stress-induced smoking in women and reducing smoking-related reinforcement in men.